Antimicrobial and plant-active 4,5-dihalopyrrole-2-carbonitriles

ABSTRACT

Phytoresponsive and antimicrobial compositions containing, as the active ingredient, a 4,5-dihalopyrrole-2-carbonitrile and methods of combatting microorganisms and plant growth comprising applying an effective antimicrobial or phytotoxic quantity of the active ingredient to a surface to be disinfected or to undesirable plant growth.

This application is a division of my prior, copending application Ser. No. 195,817, filed Nov. 4, 1971, now U.S. Pat. No. 3,864,491, patented Feb. 4, 1975.

CHEMICAL COMPOUNDS, COMPOSITIONS AND PROCESSES

This invention relates to the art of combatting microorganisms, for example bacteria and fungi, and undesirable plant growth comprising treating a surface to be disinfected or an area to be cleared of undesirable plant growth with compositions containing, as the active ingredient, a novel 4,5-dihalopyrrole-2-carbonitrile having the formula: ##SPC1##

Where X is chlorine, bromine or iodine.

In one of its aspects the instant invention relates to the novel compounds of the above formula I and to methods for the preparation thereof.

In another aspect, the invention relates to compositions for combatting microorganisms containing a 4,5-dihalopyrrole-2-carbonitrile of furmula I as the active ingredient in effective antimicrobial amount. The invention also relates to a method of combatting microorganisms comprising treating a surface to be disinfected with a composition containing an effective antimicrobial amount of the said active ingredient.

In another of its aspects, the invention relates to aquatic and terrestrial herbicidal compositions containing an effective herbicidal amount of a 4,5-dihalopyrrole-2-carbonitrile of formula I as the active ingredient.

Another aspect of the invention relates to a method of combatting undesirable terrestrial or aquatic plant growth which comprises treating an area to be cleared of such undesirable terrestrial plant growth, or a body of water to be cleared of such undesirable aquatic plant growth, with a composition containing a herbicidally effective amount of a 4,5-dihalopyrrole-2-carbonitrile of formula I as the active ingredient. When used as terrestrial herbicides, the 4,5-dihalopyrrole-2-carbonitrile-containing composition is either sprayed, dusted, or otherwise scattered as described hereinafter over an entire area to be cleared of undesirable vegetation, or alternatively individual plants can be similarly treated. When used as aquatic herbicides to destroy plant growth growing in a particular body of water, either the 4,5-dihalopyrrole-2-carbonitrile itself, or a composition containing it, is dissolved directly in the body of water in an amount, to be described hereinafter, sufficient to provide a herbicidally effective concentration of the active ingredient in the body of water being treated.

The compounds of formula I are generally prepared by direct halogenation of pyrrole-2-carbonitrile. In the case of the compounds where X is chlorine or bromine, the halogenation is advantageously carried out with the elemental halogen in glacial acetic acid at a temperature from 0°C. to around 50°C.

The compounds where X is iodine, on the other hand, are advantageously prepared by reaction of pyrrole-2-carbonitrile with a solution of iodine monochloride and sodium or potassium chloride in aqueous acetic acid at a temperature from 20°C. to around 100°C.

Alternatively, the compounds can be prepared from the corresponding 4,5-dihalopyrrole-2-carboxaldehyde by conversion of the latter to the corresponding oxime with hydroxylamine using standard procedures known in the art, and conversion of the oxime to the corresponding nitrile by reaction of the oxime with acetic anhydride at a temperature from 40°C. to around 100°C. This latter method is illustrated by the following reaction sequence: ##SPC2##

where X has the meanings given above. The 4,5-dihalopyrrole-2-carboxaldehydes in turn are prepared by direct halogenation of pyrrole-2-carboxaldehyde by methods similar to those described above for the halogenation of pyrrole-2-carbonitrile to the corresponding 4,5-dihalopyrrole-2-carbonitrile.

The compounds of the invention are formulated for use as antimicrobial agents by preparing a dilute solution in an organic medium in which the compounds are soluble, for example ethyl alcohol, acetone, dimethylsulfoxide, and the like, and are applied to a surface to be disinfected, or which is susceptible to contamination, by conventional means such as spraying, swabbing, immersion, and the like. Alternatively, the compounds can be formulated as ointments or creams by incorporating them in conventional ointment or cream bases, as alkylpolyether alcohols, cetyl alcohol, stearyl alcohol and the like, or as jellies by incorporating them in conventional jelly bases such as glycerin and tragacanth. They can also be formulated for use as aerosol sprays or foams.

The undesired microorganisms against which the instant compounds are effective may be pathogenic or not but whose presence is unwanted and thus include bacteria, fungi, protozoa, algae, and various other forms of microorganisms well-known to microbiology.

The compounds of the invention are formulated for use as either pre-emergent or post-emergent terrestrial herbicides or as aquatic herbicides by mixing the pure active ingredient with conventional pest control and herbicidal adjuvants, modifiers, diluents or conditioning agents so that they may be formulated as solutions, emulsions, dispersions, dusts or wettable powders.

Liquid formulations of the active compounds according to the present invention for direct herbicidal spraying may be made, for example, with water or water emulsions, petroleum fractions, liquid aliphatic or aromatic alcohols, esters, glycols or ketones and the like. These liquid formulations can be solutions, dispersions, emulsions or wettable powder dispersions and, if needed, may contain surface active agents, e.g., wetting agents, dispersing agents, emulsifying agents and the like, in sufficient amounts to impart the desired characteristics to the formulation.

Aqueous herbicidal formulations, for example, can be made by adding water to emulsion concentrates, pastes or wettable spray powders of the active ingredients. The wetting, emulsifying or dispersing agents may be either anionic, cationic, nonionic or mixtures thereof. Suitable wetting agents are organic compounds capable of lowering the surface tension of water and include conventional soaps such as the water-soluble salts of long-chain carboxylic acids; amine soaps, such as amine salts of long-chain carboxylic acids; sulfonated animal, vegetable and mineral oils; quaternary salts of high molecular weight acids; rosin soaps such as salts of abietic acid, sulfuric acid salts of high molecular weight organic compounds; algin soaps; and simple and polymeric compositions having both hydrophobic and hydrophilic functions.

Herbicidal dusts may be prepared by mixing or grinding the active substance with a solid carrier material such as talc, diatomaceous earth, kaolin, bentonite, calcium carbonate, boric acid, calcium phophate, wood, flour, cork, dust, carbon, and the like. Scatterable granules may be obtained, for example, by using ammonium sulfate as carrier material. Alternatively, carrier materials may be impregnated with solutions of the active substances in liquid solvents. Powder preparations or pastes which can be suspended in water and used as sprays may be obtained by adding wetting agents and protective colloids. Different forms of application may be better adapted to the various purposes for which the active substances are to be used by the addition of substances which improve dispersion, adhesion, resistance to rain, and penetrative power such as fatty acids, resins, wetting agents, emulsifying agents, glue and the like. Similarly, the biological spectrum may be broadened by the addition of other substances having bactericidal, fungicidal and plant growth regulating properties and also by combination with fertilizers.

Optimum pre- and post-emergent herbicidal action is obtained using the compounds of the invention at application rates from 1.0 to 8.0 pounds per acre, while optimum aquatic herbicidal activity is obtained using a solution concentration of the active ingredient of from about 1.0 to 40 parts per million.

The following examples illustrate the best mode of making and using the instant invention.

EXAMPLE 1 4,5-Dichloropyrrole-2-carbonitrile

To a solution of 33.5 g. (0.47 mole) of hydroxylamine hydrochloride and 67 g. (0.48 mole) of sodium acetate trihydrate in 130 ml. of water was added 40 g. (0.42 mole) of pyrrole-2-carboxaldehyde. The mixture was shaken vigorously for five minutes, cooled in a refrigerator for several days, filtered, and dried giving 45.5 g. of pyrrole-2-carboxaldoxime, m.p. 165°-168°C.

The latter was treated with 150 ml. of acetic anhydride, and after the initial exothermic reaction had subsided, the mixture was stirred and heated slowly to reflux for 20 minutes. The mixture was then cooled and poured into 1500 ml. of water, the mixture extracted with diethyl ether, and the combined extracts charcoaled, concentrated and distilled in vacuo, giving a total of 19.0 g. of pyrrole-2-carbonitrile, b.p. 133°-145°C./25mm.

The latter (10 g., 0.11 mole), dissolved in 40 ml. of glacial acetic acid, was treated slowly with stirring with a solution of 15.6 g. (0.22 mole) of chlorine dissolved in 300 ml. of glacial acetic acid. The mixture was stirred for an hour and a half, concentrated to a small volume in vacuo, the residue dissolved in diethyl ether, and the organic solution washed with aqueous sodium bicarbonate until the aqueous layer was slightly basic. The organic solution was then dried with anhydrous sodium sulfate, concentrated to dryness and the residue recrystallized from a diethyl ether/hexane mixture giving 9.0 g. of 4,5-dichloropyrrole-2-carbonitrile, m.p. 144°-146°C.

EXAMPLE 2 4,5-Dibromopyrrole-2-carbonitrile

A solution of 25 g. (0.099 mole) of 4,5-dibromopyrrole-2-carboxaldehyde [prepared according to the method of Anderson et al., Can. J. Chem. 43(2), 409-414 (1965)] and 10.5 g. (0.15 mole) of hydroxylamine hydrochloride in 100 ml. of ethanol was heated on a steam bath with stirring for 5 minutes until all solid material had dissolved. The resulting solution was treated with a solution of 10.5 g. of potassium carbonate in 20 ml. of water, heating and stirring was continued for another 10 minutes, and the mixture was poured into 500 ml. of water. The solid which separated was collected and dried in a vacuum oven at 60°C. giving 24.0 g. of 4,5-dibromopyrrole-2-carboxaldoxime, m.p. 150°-152°C.

The latter (19 g., 0.07 mole) was dissolved in 100 ml. of acetic anhydride and the mixture heated on a steam bath for 10 minutes. Concentration of the mixture to dryness in vacuo gave a black residue which was dissolved in diethyl ether. The ether solution was dried over sodium sulfate, charcoaled, concentrated to a small volume, and the solid which separated was recrystallized several times from diethyl ether/hexane to give 12.3 g. of 4,5-dibromopyrrole-2-carbonitrile, m.p. 172°-174°C. (uncorr.)

EXAMPLE 3 4,5-Diiodopyrrole-2-carbonitrile

A solution of 9.2 g. (0.10 mole) of pyrrole-2-carbonitrile in 100 ml. of glacial acetic acid was stirred on a steam bath while 45 ml. of a 4.68N aqueous solution of iodine monochloride/sodium chloride was added slowly over a period of about 15 minutes. The mixture was stirred at 50°C. for about four hours, and the precipitate which had separated was collected and dissolved in diethyl ether. The organic solution was washed first with 200 ml. of water, then with 400 ml. of saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated to dryness to give a solid residue. Recrystallization of the latter from ethyl acetate/hexane afforded 16.5 g. of 4,5-diiodopyrrole-2-carbonitrile, m.p. 211°-213°C. (uncorr.)

Anti-bacterial and anti-fungal activities for the compounds were established using standard serial dilution techniques as described by Goss and Cimijotti, Applied Microbiology, 16 1414-1416 (1968). The minimum (bactericidal and fungicidal) inhibitory concentrations (MIC) of the compounds thus tested as solutions against a variety of bacteria including Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Proteus vulgaris and against such fungi as Trichophyton mentagrophytes, Aspergillus niger, and Candida albicans were found to be in the range from 8.0 to 125 mcg./ml.

Pre-emergence herbicidal activity for the compounds of the invention was established in an initial screening procedure described as follows: Test crop seeds of five different species of plant growth (lima beans, Dent corn, lettuce, mustard and crabgrass, which were selected as representative of the major classes of mono- and dicotyledonous plants) were planted in 8×6×3 inches flat-bed trays containing two to three inches of sandy loam soil. Within twenty-four hours after planting, an aqueous acetone solution of the test compound was sprayed on the soil at a rate of 8 pounds of test agent per acre. The plants were maintained in a greenhouse and watered regularly for two weeks, after which time the phytotoxicity of the test compound was recorded by examining individual plant species for percent kill and assigning a vigor rating to the surviving members of the species according to the following scale:

5 = plants normal

4 = slight injury

3 = moderate injury; plants expected to recover

2 = moderate to severe injury; plants not expected to recover

1 = severe injury; plants will not recover.

Untreated control plants were maintained in every test carried out. The results thus obtained using the compounds of Examples 1, 2 and 3 above are given in TABLE A below.

                  TABLE A                                                          ______________________________________                                         TEST     Example 1   Example 2   Example 3                                     PLANT                                                                          SPECIES  Vigor   %Kill   Vigor %Kill Vigor %Kill                               ______________________________________                                         Lima Bean                                                                               5       0       3 a b 30    5     0                                   Dent Corn                                                                               5       0       4 a   0     5     0                                   Lettuce          100           100   5     0                                   Mustard  3       0       2     90    5     0                                   Crabgrass        100     2     90    5     0                                   ______________________________________                                          a Stunted                                                                      b Desiccation                                                            

Using the same test plant species and the same procedure used in the initial pre-emergence herbicidal screening test described above, the compound of Example 1 (4,5-dichloropyrrole-2-carbonitrile) was reevaluated for pre-emergence herbicidal activity at a rate of 8 pounds per acre and submultiples thereof, i.e. 4 pounds/acre, 2 pounds/acre, and 1 pound/acre. The results thus obtained are given in TABLE B below.

                                      TABLE B                                      __________________________________________________________________________     TEST   1.0 lb/A                                                                               2.0 lb/A                                                                               4.0 lb/A                                                                               8.0 lb/A                                        PLANT                                                                          SPECIES                                                                               Vigor                                                                              %Kill                                                                              Vigor                                                                              %Kill                                                                              Vigor                                                                              %Kill                                                                              Vigor                                                                              %Kill                                       __________________________________________________________________________     Lima Bean                                                                             3   0   4   0       100 2   70                                          Dent Corn                                                                             4   0   5   0   4   0   3   0                                           Lettuce                                                                               4   0       100     100     100                                         Mustard                                                                               4   0   4   0   2   90  2   30                                          Crabgrass                                                                             3   0   1   95      100     100                                         __________________________________________________________________________

Post-emergence herbicidal activity for the compounds of the invention was established in an initial screening procedure described as follows: Test crop seeds of the same plant species used in the pre-emergence herbicidal tests were planted in 8× 6=3 inches shallow flat-bed trays containing two to three inches of a loam soil. The growth trays were maintained in a greenhouse and watered regularly for approximately two weeks. When the first trifoliate leaves of the bean plants began to unfold, the test plants were removed from the greenhouse and sprayed with an aqueous acetone solution of the test compound at a rate of 8 pounds of the test compound per acre. The plants were maintained in the greenhouse and watered regularly for an additional two weeks, after which time the phytotoxicity of the test compound was recorded by noting the percent kill and assigning a vigor rating to surviving plants as described above. As in other tests described previously, untreated control plants were maintained in every test. The results thus obtained are given in TABLE C below.

                  TABLE C                                                          ______________________________________                                         TEST     Example 1   Example 2   Example 3                                     PLANT                                                                          SPECIES  Vigor   %Kill   Vigor %Kill Vigor %Kill                               ______________________________________                                         Lima Bean    100 a           100   2 a   60                                    Dent Corn    100 a   3        30 a 4     0                                     Lettuce      100 a           100         100                                   Mustard      100 a   2        70         100                                   Crabgrass    100 a           100         100                                   ______________________________________                                          a Desiccation                                                            

Using the same test plant species and the same procedure used in the initial post-emergence herbicidal screening test described above, the compound of Example 1 (4,5-dichloropyrrole-2carbonitrile) was reevaluated for post-emergence herbicidal activity at a rate of 8 pounds per acre and submultiples thereof, i.e. 4 pounds/acre, 2 pounds/acre, and 1 pound/acre. The results thus obtained are given in TABLE D below.

                                      TABLE D                                      __________________________________________________________________________     TEST   1.0 lb/A                                                                               2.0 lb/A                                                                               4.0 lb/A                                                                               8.0 lb/A                                        PLANT                                                                          SPECIES                                                                               Vigor                                                                              %Kill                                                                              Vigor                                                                              %Kill                                                                              Vigor                                                                              %Kill                                                                              Vigor                                                                              %Kill                                       __________________________________________________________________________     Lima Bean                                                                             3   60  2    70 2    70     100                                         Dent Corn                                                                             3    0  3    30 2    70 2    70                                         Lettuce    100     100     100     100                                         Mustard                                                                               3    20 3    70 2    90     100                                         Crabgrass                                                                             2    90     100     100     100                                         __________________________________________________________________________

For the purpose of determining the aquatic herbicidal activity of the compounds of the invention, a nutrient solution constituted as follows was prepared:

    Component                 Conc. (g/l)                                          ______________________________________                                         KNO.sub.3                 0.202                                                Ca(NO.sub.3).sub.2.4H.sub.2 O                                                                            0.709                                                KH.sub.2 PO.sub.4         0.136                                                MgSO.sub.4                0.120                                                CaCl.sub.2.2H.sub.2 O     0.441                                                KC1                       0.149                                                MgCl.sub.2.6H.sub.2 O     0.203                                                Thiamine                  0.0001                                               Pyridoxine                0.0008                                               Nicotinamide              0.0008                                               H.sub.3 BO.sub.3          0.0001                                               MnCl.sub.2.4H.sub.2 O     0.0001                                               ZnSO.sub.4.7H.sub.2 O     0.0003                                               CuSO.sub.4.5H.sub.2 O     0.0001                                               Na.sub.2 MoO.sub.4.H.sub.2 O                                                                             0.0001                                               Iron Versenol (N-carboxymethyl)-                                               N'- (2-hydroxyethyl)-N,N'-ethylene-                                            diglycine iron salt)      0.005                                                ______________________________________                                    

A sufficient quantity of the test compound to provide a concentration of 5 ppm of active ingredient was dissolved in about 800 ml. of the nutrient solution. To this solution was added 25 to 30 duckweed plants (Lemna minor L.) and three snails (Helisoma trivolvis). The solutions with the plants and snails were maintained throughout the test at 25°C. under artificial light. Twenty-four hours later, the solutions were examined for snail mortality, and nine days later, the percent reduction of growth of the plants, relative to an untreated control, was recorded. The test solutions were also examined for presence of algae, plant growth aberration, and chlorosis. The results thus obtained are given in TABLE E below.

                  TABLE E                                                          ______________________________________                                         Example        %Kill        Snails                                                                         Killed                                             ______________________________________                                         1              100          no                                                 2              100 a        --                                                 3              100 a        --                                                 ______________________________________                                          a Algicidal                                                              

The aquatic herbicidal activity of the compound of Example 1 was reevaluated according to the following procedure: A sufficient amount of the test compound was dissolved in about three liters of tap water in a glass container, and test plants were placed in the aqueous solution. Test plants which normally grow from a lake or stream bottom were first rooted in a 21/2 inch flowerpot containing fertilized silt loam/sandy loam soil, and free floating plants were placed randomly in the aqueous solution. The container holding the toxicant solution, test plants and a few snails was placed under artificial light in a growth chamber, maintained at about 25°C., and after periods of 1, 2, 3, and 4 weeks, during which the solution volume in the test containers was maintained, test plants were examined for kill or reduction of growth compared to plants grown in an aqueous, untreated environment. The plants were rated on a scale of 1 to 5 as indicated above, and in addition, the growth of algae, plant aberration, and snail kill were recorded. The results thus obtained are given in TABLE F below, where the initials P., M., E., C., A., D., and W., at the head of the various columns represent the respective aquatic plants, purslane, milfoil, elodea, crowfoot, arrowhead, duckweed, and wolffia.

                  TABLE F                                                          ______________________________________                                         Concen. Week of   Growth Reduction   Snails                                     (ppm)  test      P.    M.  E.  C.  A.  D.  W.   Dead                          ______________________________________                                          40     one       2     2   2   2   2   2   2    yes                                   two       2     2   2   2   2   2   1    yes                                   three     1     1   1   1   1   3   2    yes                                   four      1     1   2   1   1   3   1    yes                            20     one       2     2   2   2   2   3   3    no                                    two       2     2   2   2   2   3   3    yes                                   three     1     1   1   1   1   4   3    yes                                   four      1     1   2   1   1   5   3    yes                            10     one       2     2   2   2   3   3   3    no                                    two       1     1   2   2   2   3   2    yes                                   three     2     2   2   2   2   3   2    yes                                   four      1     1   2   1   2   5   3    yes                            5      one       3     4   4   2   4   4   3    no                                    two       2     3   2   1   2   4   4    yes                                   three     2     2   2   2   3   3   4    yes                                   four      1     1   2   1   3   4   1    yes                            1      one       2     2   3   2   3   1   1    yes                                   two       1     1   1   1   1   2   2    yes                                   three     1     1   1   1   1   2   2    yes                                   four      1     1   1   1   2   2   1    yes                            0.5    one       5     5   5   5   5   5   5    no                                    two       5     5   5   5   5   5   5    no                                    three     5     5   5   5   5   5   5    no                                    four      5     5   5   5   5   5   5    no                            Control all       5     5   5   5   5   5   5    no                            ______________________________________                                     

I claim:
 1. A compound having the formula ##SPC3##
 2. 4,5-Dichloropyrrole-2-carbonitrile according to claim 1 where X is
 3. 4,5-Dibromopyrrole-2-carbonitrile according to claim 1 where X is
 4. 4,5-Diiodopyrrole-2-carbonitrile according to claim 1 where X is iodine 